Histologically Proven Bronchial Neuroendocrine Tumors in MEN1: A GTE 51-Case Cohort Study.

OBJECTIVE: To evaluate the natural history of MEN1-related bronchial endocrine tumors (br-NETs) and to determine their histological characteristics, survival and causes of death. br-NETs frequency ranges from 3 to 13% and may reach 32% depending on the number of patients evaluated and on the criteria required for diagnosis. METHODS: The 1023-patient series of symptomatic MEN1 patients followed up in a median of 48.7 [35.5-59.6] years by the Groupe d'étude des Tumeurs Endocrines was analyzed using time-to-event techniques. RESULTS: br-NETs were found in 51 patients (4.8%, [95% CI 3.6-6.2%]) and were discovered by imaging in 86% of cases (CT scan, Octreoscan, Chest X-ray, MRI). Median age at diagnosis was 45 years [28-66]. Histological examination showed 27 (53%) typical carcinoids (TC), 16 (31%) atypical carcinoids (AC), 2 (4%) large cell neuroendocrine carcinomas (LCNEC), 3(6%) small cell neuroendocrine carcinomas (SCLC), 3(6%) TC associated with AC. Overall survival was not different from the rest of the cohort (HR 0.29, [95% CI 0.02-5.14]). AC tended to have a worse prognosis than TC (p = 0.08). Seven deaths were directly related to br-NETs (three AC, three SCLC and one LCNEC). Patients who underwent surgery survived longer (p = 10-4) and were metastasis free, while 8 of 14 non-operated patients were metastatic. There were no operative deaths. CONCLUSIONS: Around 5% of MEN1 patients develop br-NETs. br-NETs do not decrease overall survival in MEN1 patients, but poorly differentiated and aggressive br-NETs can cause death. br-NETs must be screened carefully. A biopsy is essential to operate on patients in time.

[Epidemiology, treatment and follow-up of central nervous system hemangioblastomas in von Hippel-Lindau disease]. / Épidémiologie, traitement et suivi des hémangioblastomes du système nerveux central dans le cadre de la maladie de von Hippel-Lindau.

INTRODUCTION: Central nervous system (CNS) hemangioblastomas (HGB) are rare vascular tumors. The goal of this study was to analyze their epidemiology, treatment and prognosis in association with von Hippel-Lindau (VHL) disease. METHODS: We retrospectively reviewed a series of patients treated in our department for a CNS HGB with VHL disease between 1996 and 2008. We analyzed pre- and postoperative clinical and radiological characteristics, number of visceral lesions (fundoscopy, abdomino-pelvian CT, metanephrines), clinical course (modified Rankin Scale and McCormick scale) and late prognosis (Kaplan-Meier survival curves). RESULTS: We studied 19 cases (sex-ratio 0.9, mean age 36). The mean time to diagnosis was 61days. The main symptom was intracranial hypertension for cerebellar lesions (7/15) and a sensitive-motor deficit for medulla oblongata (2/5) or spinal lesions (5/11). Preferred locations were cerebellum (15/31), often nodulo-cystic appearance, followed by spinal cord (11/31), frequently coming with adjacent syringomyelia. Multiple locations and visceral lesions were found in two-third of the cases. Surgical removal was complete in more than three-quarter of the cases. Mean follow-up duration was 9years. Postoperative mortality rate was 16%. In cerebellar and medulla oblongata locations together, final mRS was ≤1 in 17 of the 20 cases. In spinal cord locations, final McCormick score was ≤2 in all the cases. After delayed follow-up, about two-third of patients experienced recurrence or new progressive CNS lesions. CONCLUSION: HGB are rare CNS tumors. VHL disease should be considered when an HGB is diagnosed before 30, is located at the spinal cord, comes with multiple other CNS lesions or with typical peripheral lesions. Microsurgical removal is the gold standard treatment and can offer good functional results.

[Pheochromocytomas and paragangliomas in pregnancy: About four cases and key messages on management]. / Phéochromocytomes et paragangliomes pendant la grossesse : à propos de quatre cas et messages clés sur la prise en charge.

OBJECTIFS: The diagnosis of a pheochromocytoma or paraganglioma secreting during pregnancy is a rare and serious situation, involving maternal-fetal prognosis. The purpose of this case series is to discuss the management of these patients. METHODS: This is a retrospective study of cases of pheochromocytoma (n=2) or paraganglioma (n=2) managed during pregnancy between 2013 and 2020 in one center (Lille, France). RESULTS: We report four cases of patients with a diagnosis of pheochromocytoma or paraganglioma during pregnancy, at respectively 4, 28, 31 and 34 weeks of amenorrhea (AS). Their pregnancies were affected by a sudden onset of hypertension sometimes associated with headaches, sweating, and palpitations. All patients delivered by Caesarean section after calcium channel blocker impregnation, with a good outcome. Tumor removal took place at a distance from delivery for each patient. CONCLUSIONS: The therapeutic strategy includes antihypertensive treatment with calcium channel blockers or alphablockers and surgical curative treatment linked to gestational age. Multidisciplinary management as well as early diagnosis can improve the maternal-fetal prognosis. The preferred way of delivery is Caesarean section, but vaginal delivery can also be considered. Removal should ideally take place at a distance from the birth. The analysis of these cases has led to the development of a protocol for monitoring and management of parturients with diagnosis of pheochromocytoma or paraganglioma during pregnancy.

Does the RET variant G691S influence the features of sporadic medullary thyroid carcinoma?

OBJECTIVE: The RET (rearranged during transfection) proto-oncogene G691S variant is over-represented in the germline of patients with sporadic medullary thyroid carcinoma (sMTC) vs. normal controls but so far is not associated with any medical or pathological features of the tumour. The aim of our study was to assess the influence of this variant on the age of onset, clinical, biological and pathological features of sMTC. DESIGN AND PATIENTS: One hundred patients with histologically proven MTC, for whom the germline genetic analysis of RET was negative and medical records were available, were included in the study. RESULTS: Patients with the heterozygous GS variant or the homozygous SS variant (n = 36) were on average 8.0 years younger than patients with the wild-type GG variant (n = 64, mean age 43.9 vs. 51.9 years, P < 0.01). The former group did not differ from the wild-type group in terms of MTC size, prevalence of C-cell hyperplasia (CCH) or papillary thyroid carcinoma (PTC). However, the prevalence of an increased preoperative basal calcitonin (bCT) level (> 1000 pg/ml) was 2.75-fold higher in the patients with the GS or SS variant than in those with the wild-type variant (P < 0.001). The proportion of patients with lymph node metastases was also higher in the former group (P < 0.05). Multivariate analysis confirmed that the presence of the RET variant is independently associated with higher preoperative bCT values (P = 0.011). CONCLUSIONS: Our data demonstrate that the RET G691S variant could modulate the age of onset of sMTC as demonstrated previously for familial tumours. Moreover, this variant is an independent predictor of a higher basal calcitonin synthesis rate in patients with sMTC.

Proteomic analysis in cardiovascular diseases.

1. Cardiovascular diseases are a major cause of morbidity and mortality in western countries. The molecular mechanisms responsible for heart dysfunction are still largely unknown, except in cases of genetic defects or alteration of genes and proteins. 2. The publication of genome sequences from humans and other species has demonstrated the complexity of biology, including the finding that one gene does not encode for only one protein but for several, due to mRNA splicing and post-translational modifications. 3. Proteomic analysis can provide an overall understanding of changes in the levels of protein expression. Differential proteomics is a powerful tool for improving our understanding of integrated biochemical responses. The main techniques used are two-dimensional electrophoresis (2D-gel) and Surface-Enhanced Laser Desorption/Ionization Time of Flight (SELDI-TOF) to separate proteins associated with mass spectrometry. Bioinformatic tools make it possible to compare protein profiles obtained from diverse biological samples. 4. The combination of these approaches has proved to be particularly interesting for studying cardiovascular diseases and thereby improving our understanding of the mechanisms involved and identifying new biochemical factors and biomarkers involved in these diseases.

Nitric oxide synthase modulates angiogenesis in response to tissue ischemia.

We tested the hypothesis that endothelial nitric oxide synthase (eNOS) modulates angiogenesis in two animal models in which therapeutic angiogenesis has been characterized as a compensatory response to tissue ischemia. We first administered L-arginine, previously shown to augment endogenous production of NO, to normal rabbits with operatively induced hindlimb ischemia. Angiogenesis in the ischemic hindlimb was significantly improved by dietary supplementation with L-arginine, compared to placebo-treated controls; angiographically evident vascularity in the ischemic limb, hemodynamic indices of limb perfusion, capillary density, and vasomotor reactivity in the collateral vessel-dependent ischemic limb were all improved by oral L-arginine supplementation. A murine model of operatively induced hindlimb ischemia was used to investigate the impact of targeted disruption of the gene encoding for ENOS on angiogenesis. Angiogenesis in the ischemic hindlimb was significantly impaired in eNOS-/- mice versus wild-type controls evaluated by either laser Doppler flow analysis or capillary density measurement. Impaired angiogenesis in eNOS-/- mice was not improved by administration of vascular endothelial growth factor (VEGF), suggesting that eNOS acts downstream from VEGF. Thus, (a) eNOS is a downstream mediator for in vivo angiogenesis, and (b) promoting eNOS activity by L-arginine supplementation accelerates in vivo angiogenesis. These findings suggest that defective endothelial NO synthesis may limit angiogenesis in patients with endothelial dysfunction related to atherosclerosis, and that oral L-arginine supplementation constitutes a potential therapeutic strategy for accelerating angiogenesis in patients with advanced vascular obstruction.

Calcitonin levels do not decrease with weaning in chronic alcoholism.

OBJECTIVE: Alcohol might increase calcitonin but this assertion is mainly based on the acute effect of the drug in small animals and humans. The aim of this study was to investigate the effect of chronic alcoholic intoxication on plasma calcitonin (CT) levels. DESIGN: 20 smoking male subjects admitted to be weaned from chronic daily alcohol consumption >100 g were included after informed consent. Blood was sampled upon admission (T0) and after 5 (T5) and 21 (T21) days of alcohol weaning to measure mean erythrocyte volume, gamma-glutamyltransferase (GGT), calcium, gastrin, and CT levels. The control group consisted of 30 male subjects with daily alcohol consumption <20 g. MAIN OUTCOME: The characteristics of the alcohol group were as follows (mean +/- SD): age 41.2 +/- 13 years old; mean erythrocyte volume: 96.0 +/- 4.2 microm(3) (N: 85-95); calcium level: 94.7 +/- 3.7 mg/L (N: 85-105); gastrinemia: 59.3 +/- 14.9 ng/mL (N: <120). At T0 and T21, three alcoholic subjects had CT levels above 10 pg/mL, usually considered as the normal cut-off value. There was no correlation between CT and the different biochemical parameters at T0, T5, and T21. There was no difference between CT levels at the different stages in the alcohol group (T0: 6.4 +/- 3.6 pg/mL; T5: 6.5 +/- 5.3 pg/mL; T21: 8.4 +/- 5.6), although GGT significantly decreased with weaning duration (T0: 248 +/- 354 IU/L; T5: 211 +/- 290 IU/L; T21: 79 +/- 90 IU/L; ANOVA, p <0.05). But a significant difference was found between mean CT levels in the alcohol group and in the control group (3.1 +/- 0.7 pg/mL, p <0.0001). CONCLUSIONS: This study suggests that mean CT levels of chronically alcoholic smoking male subjects are higher than those of an age- and sex-matched control group. However, most alcoholic patients exhibited CT levels <10 pg/mL. No decrease in CT levels was noted over a short period of alcohol weaning. As CT measurement is currently recommended in thyroid nodule assessment, this finding may be important to know how to decipher borderline values of CT.

[Indications and limits of myocardial revascularization in the elderly]. / Indications et limites de la revascularisation myocardique chez le sujet âgé.

Due to the demographic evolution in our country, the management of old patients with coronary disease is of increasing concern in practice. Few studies specifically related in this age group are however available and data issued from subgroup analyses are subject to possible selection bias. The older subject candidate for myocardial revascularization is potentially at higher risk than the younger one. This higher risk should however not overshadow the benefit, which is often also more important.

Functional mitral regurgitation and chronic heart failure.

Functional mitral regurgitation (MR) frequently develops during the progression of chronic heart failure and predicts poor outcome. Impaired left ventricular (LV) function, LV remodeling associated with papillary muscle apical displacement and annular enlargement result in decreased mitral closing forces and tenting of the mitral valve at closure. Reduced closing forces and tenting both promote MR. Active myocardial ischemia, myocardial asynchronism and excessive loading conditions worsen MR at rest and during exercise. The therapeutic target in functional MR is the left ventricle and not the valve.

Contribution of genetic analysis in screening for MEN1 among patients with sporadic disease and one or more typical manifestation.

Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant hereditary syndrome (OMIM 131100) due to MEN1 gene mutations, predisposing to the development of hyperplasic and tumoral lesions of neuroendocrine tissues. Since the identification of the gene in 1997, more than 400 different mutations of MEN1 have been registered. Genotypic analysis of MEN1 remains fastidious and must be reserved to targeted situations. If the lesions appear in a familial assessed context, there is a strong argument to search for MEN1 mutation. This is not the case in a sporadic context. With experience acquired in our laboratory, we evaluated the frequency of MEN1 mutations in patients with sporadic presentations. Our aim was to better define criteria for MEN1 genotypic analysis. One hundred and twenty four blood samples from unrelated patients, who gave their written informed consent, were analyzed. These patients exhibited 1 to 4 manifestations of MEN1 without any familial context. After DNA extraction, the analysis was undertaken by PCR-sequencing of all the MEN1 coding exons and exon/intron boundaries or by PCR of the pre-screened fragments alone, a technique made possible by indirect screening mutation methods. Mutations were identified by comparing the sequences to the reference MEN1 sequence available from GENBANK (U93237.1). Mutations were identified in 19 patients, with variable prevalence according to clinical manifestations: 100% for patients with 4 manifestations, 45.5% for patients with 3 manifestations, 19% for patients with 2 manifestations and 2% for patients with only one manifestation. Mutations were: 11 point variations (58%), including 2 splicing sites and 8 frameshift mutations (42%) including 5 deletions, 2 insertions and 1 insertion/deletion; one mutation was identified twice. We showed a relationship between clinical presentation and MEN1 mutation identification, especially with the number of clinical manifestations but also with the type of manifestation. Pancreatic manifestations were significantly linked with probability of mutation. In a sporadic context with at least two established manifestations of MEN1, the overall probability of identifying a mutation was 26%, warranting MEN1 genotypic analysis.

Angiographically documented late reocclusion after successful coronary angioplasty of an infarct-related lesion is a powerful predictor of long-term mortality.

BACKGROUND: Late reocclusion of an infarct-related artery (IRA) that was patent in the early days after acute myocardial infarction (MI) is a frequent event; the reocclusion rate may be as high as 30%. Few studies have been designed to analyze the impact of late reocclusion of the IRA on late survival. METHODS AND RESULTS: We studied 528 patients who all had a patent IRA after a successful PTCA procedure 10+/-6 days after MI and who underwent systematic 6-month angiographic follow-up to assess late patency of the IRA. We compared long-term survival of patients with and without late reocclusion. Based on the results of 6-month follow-up angiography, 2 groups of patients were defined: (1) 90 patients (17%) with reocclusion (Thrombolysis In Myocardial Infarction [TIMI] flow 0 or 1) and (2) 438 patients (83%) without reocclusion. Long-term clinical follow-up was obtained for all 528 patients at a median of 5.7 years after follow-up angiography (6.4 years after PTCA). The overall actuarial 8-year total mortality rate was 13%. At the end of follow-up, there were 35 deaths (8%) among the 438 patients without reocclusion and 18 deaths (20%) among the 90 patients with reocclusion (P=0.002). The actuarial 8-year total mortality rate was 10% in patients without reocclusion and 28% in patients with reocclusion (P=0.0003). The actuarial cardiovascular mortality rate was 7% in patients without reocclusion and 25% in patients with reocclusion (P<0.0001). The impact of reocclusion on long-term mortality was greater in patients with anterior MI. CONCLUSIONS: Late IRA patency is strongly associated with long-term survival after MI. These observations should encourage prospective studies to evaluate the impact of strategies designed to prevent late reocclusion in postinfarction patients.

Basic fibroblast growth factor increases tissue factor expression in circulating monocytes and in vascular wall.

BACKGROUND: Basic fibroblast growth factor (bFGF) promotes vascular repair and angiogenesis and can induce in vitro tissue factor (TF), a potent agent initiating thrombogenesis, which probably plays a role in angiogenesis. We investigated whether bFGF administration induced TF expression by monocytes and vascular cells. METHODS AND RESULTS: We studied TF expression in normally fed (n=16) and cholesterol-fed (2% for 6 weeks, n=16) rabbits. Animals were then randomized to receive intravenous bFGF (2.5 microg twice weekly for 3 weeks) or saline injections. TF expression was evaluated in mononuclear cells from arterial blood and in aortic sections by an immunohistochemical assay using a monoclonal anti-rabbit TF antibody (activator protein 1). Monocyte TF expression was increased by bFGF administration in both normal and hypercholesterolemic rabbits (129+/-45 versus 19+/-3 mU TF/1000 monocytes, P<0.05, and 31+/-12 versus 7+/-1 mU TF/1000 monocytes, P<0.005, respectively) and was further increased by stimulation of monocytes by endotoxin in vitro. TF expression was lower in hypercholesterolemic rabbits than in normal rabbits. In the media of the vascular wall, bFGF induced strong TF expression in normal rabbits and only weak TF expression in hypercholesterolemic ones. CONCLUSIONS: This study demonstrates that systemic administration of bFGF induces an impressive increase of TF expression in circulating monocytes and in the vascular wall in normal and to a lower extent in hypercholesterolemic rabbits. The significance of this observation in terms of inducing thrombosis in vivo needs clarification.

Paraoxonase polymorphism (Gln192Arg) as a determinant of the response of human coronary arteries to serotonin.

Background-Oxidation of LDL plays a role in endothelial dysfunction. Paraoxonase, an enzyme present on HDL, protects LDL against oxidation. Paraoxonase activity is genetically determined in part, and 3 genotypes have been described with variable enzymatic activity. We hypothesized that the paraoxonase polymorphism might influence endothelial function. Methods and Results-Twenty-seven patients with clinical manifestations of coronary artery disease underwent provocative testing by intracoronary administration of serotonin. None of the coronary arteries studied had significant (>50%) stenosis. Ten patients had the QQ genotype and 17 had the QR genotype. At proximal segments, the mean percentage reduction in lumen diameter in response to serotonin was greater in QQ patients than in QR patients (10(-5) mol/L: P<0.05; 10(-4) mol/L: P<0.006). Similarly, at distal segments, constriction in response to serotonin was greater in QQ patients than in QR patients (10(-6) mol/L: P<0. 03; 10(-5) mol/L: P<0.07). Conclusions-These results suggest a higher synthesis or release of endothelium-derived relaxing factors to counteract the vasoconstrictor effect of serotonin in patients with the R allele. These findings provide evidence that the paraoxonase polymorphism may play a role in the regulation of coronary vasomotor tone.

Patency of percutaneous transluminal coronary angioplasty sites at 6-month angiographic follow-up: A key determinant of survival in diabetics after coronary balloon angioplasty.

BACKGROUND: Several reports have demonstrated a high mortality rate in diabetic patients treated by standard coronary balloon angioplasty. No clear explanation has been provided for this finding. METHODS AND RESULTS: Consecutive diabetic patients successfully treated by standard coronary balloon angioplasty (n=604) were enrolled in a follow-up program including repeated angiography at 6 months and long-term clinical follow-up. Clinical follow-up was available in 603 patients (99.8%). Twelve patients died, 2 underwent bypass surgery before scheduled repeated angiography, and 76 declined angiography. Determinants of long-term mortality were analyzed in the 513 patients with angiography at 6 months and long-term clinical follow-up (mean follow-up, 6.5+/-2.4 years). On the basis of the results of repeated angiography, 3 groups of patients were defined: group 1, 162 patients without restenosis (32%); group 2, 257 patients with nonocclusive restenosis (50%); and group 3, 94 patients with coronary occlusion (18%). Overall actuarial 10-year mortality rate was 36%. Actuarial 10-year mortality was 24% in group 1, 35% in group 2, and 59% in group 3 (P:<0.0001). Multivariate analysis demonstrated that coronary occlusion was a strong and independent correlate of long-term total mortality (hazard ratio, 2.16; 95% CI, 1.43 to 3.26; P:=0.0003) and cardiac mortality (hazard ratio, 2.38; 95% CI, 1.48 to 3.85; P:=0.0004). CONCLUSIONS: This study demonstrates that restenosis, especially in its occlusive form, is a major determinant of long-term mortality in diabetic patients after coronary balloon angioplasty.

Clinical characteristics and angiographic follow-up of patients undergoing early or late repeat dilation for a first restenosis.

OBJECTIVE: The aim of this study was to analyze the angiographic rate of recurrent restenosis in patients who underwent repeat coronary angioplasty for a first restenosis within 3 months or greater than 3 months after the first procedure. BACKGROUND: Several studies that have examined risk factors for restenosis after coronary angioplasty have suggested that a short interval between a first angioplasty and a repeat procedure is associated with an increased risk for a second restenosis. METHODS: Between January 1981 and December 1990, 423 patients underwent a repeat coronary angioplasty procedure because restenosis had occurred at the site of a successful first angioplasty procedure. The clinical characteristics, immediate outcome and angiographic rate of recurrent restenosis were compared in patients who underwent repeat dilation within 3 months (early redilation group, n = 77) or greater than 3 months (late redilation group, n = 346) after the first procedure. RESULTS: The incidence of unstable angina at the time of the repeat procedure was significantly higher in the patients who underwent early redilation (42% vs. 8%, p = 0.0001). The procedural success rate (95%) and complication rate were similar in both groups. Follow-up angiography was performed in 86% of patients with an initially successful procedure. The incidence of restenosis was significantly higher in the group that underwent early redilation (56% vs. 37%, p = 0.007) and was similar in patients in this group who presented with stable (55%) or unstable (57%) angina. CONCLUSIONS: Rapidly recurring coronary stenoses have an extremely high rate of restenosis when again treated by coronary angioplasty, irrespective of the clinical presentation at the time of repeat dilation. The outcome in patients with early restenosis who have stable angina might be improved by delaying the repeat procedure.

Restenosis, late vessel occlusion and left ventricular function six months after balloon angioplasty in diabetic patients.

OBJECTIVES: We studied angiographic outcome and its predictors after traditional coronary balloon angioplasty in diabetics. We further examined whether changes in ejection fraction were influenced by the status of the dilated site(s) at follow-up. BACKGROUND: Recent studies have suggested that diabetics have a particularly poor outcome after balloon angioplasty. The reasons for this observation are not known. METHODS: We investigated procedural and six-month angiographic outcome, analyzed by quantitative coronary angiography, and left ventricular function in 485 consecutive diabetics (627 lesions) treated by balloon angioplasty without stent implantation. RESULTS: The procedure was successful in 455 (94%) patients; angiographic follow-up was available in 377 patients (83%). At follow-up, the rates of restenosis and total occlusion were 62% and 13%, respectively. Five independent predictors of restenosis were identified: the presence of organ damage, a saphenous vein graft (SVG) angioplasty, a bifurcation lesion, a Thrombolysis in Myocardial Infarction (TIMI) flow <3 preprocedure and the degree of residual stenosis. Four independent predictors of vessel occlusion were identified: treatment with insulin, a SVG angioplasty, a TIMI flow <3 preprocedure and the degree of residual stenosis after angioplasty. Late vessel occlusion at angioplasty site(s) was observed in 15% of patients, ranging from 11% for a one-site procedure to 37% for a three-site procedure. This complication was associated with a decrease in ejection fraction at follow-up (-6.2 +/- 9.9%, p = 0.0001), whereas no significant change was observed in patients without occlusion. CONCLUSIONS: This study shows that late vessel occlusion is a frequent mode of restenosis in diabetic patients and is associated with a significant decrease in ejection fraction. This could partly explain the poor long-term clinical outcome reported in such patients after traditional balloon angioplasty.

Role of nitric oxide in restenosis after experimental balloon angioplasty in the hypercholesterolemic rabbit: effects on neointimal hyperplasia and vascular remodeling.

OBJECTIVES: The purpose of this study was to assess the effects of L-arginine and N(G)-nitro-L-arginine methyl ester (L-NAME) on neointimal hyperplasia and vascular remodeling after balloon angioplasty in the hypercholesterolemic rabbit. BACKGROUND: Restenosis after balloon angioplasty is a consequence of both neointimal hyperplasia and vessel remodeling. Nitric oxide inhibits neointimal hyperplasia, but its effect on vessel remodeling is unknown. METHODS: Six weeks after induction of bilateral iliac atherosclerosis, 48 rabbits underwent successful angioplasty in 75 vessels. Eight rabbits (acute group) were sacrificed immediately after angioplasty. The remaining animals received either placebo (chronic control group), or a diet supplemented with either L-arginine (1.5 g/kg/day), or L-NAME (15 mg/kg/day) for 4 weeks after angioplasty. RESULTS: The intimal area was significantly greater in the chronic control group compared to the acute group (2.60+/-1.03 mm2 vs. 1.35+/-0.62 mm2). This increase in intimal area was lower in the L-arginine group (1.79+/-0.61 mm2), and greater in the L-NAME group (3.23+/-0.92 mm2). The area circumscribed by the internal elastic lamina (IEL) increased significantly in the control group compared to the acute group (from 2.52+/-0.66 to 3.33+/-0.85 mm2); a more marked increase occurred in the L-NAME group (3.90+/-0.85 mm2). By contrast, IEL area was unchanged in the L-arginine group (2.41+/-0.62 mm2). As a result, there was no significant difference in lumen area after 4 weeks in the chronic groups (control: 0.74+/-0.38 mm2; L-arginine: 0.50+/-0.43 mm2; L-NAME: 0.48+/-0.42 mm2). CONCLUSIONS: Our results demonstrate that L-arginine inhibits whereas L-NAME stimulates neointimal hyperplasia after experimental balloon angioplasty in the hypercholesterolemic rabbit. However, the lack of vessel enlargement in the L-arginine group resulted in a similar final lumen size in the L-NAME and L-arginine groups.

Predictors of restenosis after coronary stent implantation.

OBJECTIVES: We sought to determine predictors of restenosis after coronary stenting (CS) in a consecutive series of patients. BACKGROUND: Although stenting in highly selected patient groups reduces restenosis, the results of stenting in a heterogeneous patient group and the effects of clinical and procedural factors on stent restenosis are currently unclear. METHODS: We analyzed the 6-month angiographic outcome of 500 lesions in 463 consecutive patients undergoing successful CS. Clinical, qualitative and quantitative angiographic variables were correlated with restenosis assessed as both a binary and a continuous variable. RESULTS: Restenosis, defined as the presence of >50% diameter stenosis in the dilated segment, was present in 105 (26%) of the 405 lesions with angiographic follow-up. The mean late lumen loss during the follow-up period was 0.79+/-0.64 mm. Implantation of multiple stents (p < 0.0001) and a high acute gain (p < 0.0002) were independently associated with a higher late lumen loss. In contrast, the use of high inflation pressure (p < 0.02) and Palmaz-Schatz stents (p < 0.005) was independently associated with a lower late lumen loss. When restenosis was defined as a qualitative variable, implantation of multiple stents (p < 0.001), stenosis length (p < 0.01), small reference diameter (p < 0.02) and stent type other than Palmaz-Schatz (p < 0.01) were independent predictors of restenosis. None of the clinical variables tested was associated with restenosis. CONCLUSIONS: Coronary stenting in an unselected patient group is associated with an acceptable restenosis rate. Although some risk factors were identified, the risk of restenosis was not related to most of the variables tested. This suggests that the superiority of CS over balloon angioplasty, in terms of restenosis, might also apply to subgroups of patients that were not included in the recent randomized studies.

The angiotensin II type 1 receptor gene polymorphism is associated with coronary artery vasoconstriction.

OBJECTIVES: This study sought to assess the potential association of the angiotensin-converting enzyme (ACE) and angiotensin II type 1 (AT1) receptor gene polymorphisms on coronary vasomotion in humans. BACKGROUND: Abnormal coronary vasomotion plays a role in the clinical expression of coronary atherosclerosis. The components of the renin-angiotensin system are important determinants of vasomotor tone. Furthermore, epidemiologic evidence suggests that these components are involved in the pathogenesis of coronary artery disease. Indeed, two genetic polymorphisms of the ACE and AT1 receptor genes were synergistically associated with the occurrence of myocardial infarction. The influence of these genetic polymorphisms on the risk of myocardial infarction may be related, at least in part, to a deleterious effect on coronary vasomotion. METHODS: We studied the response of angiographically normal human coronary arteries after intravenous injection of methylergonovine maleate, a potent vasoconstrictor whose effects have been previously explored in various aspects of coronary artery disease. We characterized the ACE and AT1 receptor genotypes in a consecutive series of 140 patients with normal coronary arteries. Coronary vasomotion was assessed with quantitative coronary angiography. RESULTS: No effect of the ACE gene polymorphism was detected. Conversely, the patients carrying the AT1 receptor CC genotype (n = 13) had significantly greater vasoconstriction in distal coronary vessels (p < 0.009). CONCLUSIONS: The AT1 receptor gene polymorphism is associated with coronary vasomotion in humans.

The French Randomized Optimal Stenting Trial: a prospective evaluation of provisional stenting guided by coronary velocity reserve and quantitative coronary angiography. F.R.O.S.T. Study Group.

OBJECTIVES: We sought to make a prospective comparison of systematic stenting with provisional stenting guided by Doppler measurements of coronary velocity reserve and quantitative coronary angiography. BACKGROUND: Despite the increasing use of stents during percutaneous transluminal coronary angioplasty, it is unclear whether systematic stenting is superior to a strategy of provisional stenting in which stents are placed only in patients with unsatisfactory results or as a bail-out procedure. METHODS: Two hundred fifty-one patients undergoing elective coronary angioplasty were randomly assigned either to provisional stenting (group 1, in which stenting was performed if postangioplasty coronary velocity reserve was <2.2 and/or residual stenosis > or =35% or as bail-out) or to systematic stenting (group 2). The primary end point was the six-month angiographic minimal lumen diameter (MLD). Major adverse cardiac events were secondary end points (death, acute myocardial infarction and target lesion revascularization). RESULTS: Stenting was performed in 48.4% of patients in group 1 and 100% of patients in group 2 (p<0.01). Six months after angioplasty, the MLD did not differ between groups (1.90+/-0.79 mm vs. 1.99+/-0.70 mm, p = 0.39), as was the rate of binary restenosis (27.1% vs. 21.4%, p = 0.37). Among patients with restenosis, 13/32 (40.6%) in group 1 but 100% (25/25) in group 2 had in-stent restenosis (p<0.01). Target lesion revascularization (15.1% vs. 14.4% in groups 1 and 2 respectively, p = 0.89) and major adverse cardiac events (15.1% vs. 16.0%, p = 0.85) were not significantly different. CONCLUSIONS: Systematic stenting does not provide superior angiographic results at six months as compared with provisional stenting.